Unlike other organs, the brain exists under a particular environment: it is immersed in the cerebrospinal fluid within rigid bodies such as the skull and cerebral pachymeninx. It is one of the most active organs in energy metabolism and shows the highest rate of oxygen consumption out of all organs. Most of energy required for the brain neurons are derived from oxygen and glucose. These energy sources are scarcely stored in the brain and continuously supplied by the blood. Therefore, in the cerebral blood vessel itself, the mechanism for controlling cerebral blood flow develops well to stably supply energy sources for brain tissues and to maintain an external environment of the brain neurons constant. When the homeostatic mechanism in the brain is damaged by physical pressure such as hematoma, cerebral tumor or cerebral injury, the brain is placed in the situation of ischemia, and their neurons are exposed to hypoxic situation and cannot function properly. When the brain neurons fall into oxygen-deficiency state (hereinafter referred to as "cerebral hypoxia"), the permeability of membranes of the brain neurons changes; so the invasion of the extracellular fluid causes edema. When cerebral edema grows to a certain extent, the intracranial pressure rises to cause cerebral circulatory disturbance. The augmentation of cerebral hypoxia and the deficiency of glucose and accumulation of its metabolites, which are due to the cerebral circulatory disturbance, enlarge cerebral edema. As a result, the growth of cerebral edema and the rise of intracranial pressure are further accelerated; the compression of brain stem and the disturbance in pass of the cerebrospinal fluid occur and lead to the formation of a vicious circle of the augmentation of cerebral hypoxia, the growth of cerebral edema and the rise of intracranial pressure. Consequently, the lesion is enlarged so that even healthy brain tissues become hypoxic. In the end, the brain falls into the situation of circulatory insufficiency; so the damage is severe. This is the reason why cerebral hypoxia is called the common denominator of most diseases due to cerebral circulatory disturbances [Eur. Neurol.,17 (Supple.1), 113-120 (1978)].
With an increase of the proportion of the elderly in population, senile dementia is becoming a major problem of society. The great majority of senile dementia are composed of cerebrovascular dementia, Alzheimer-type dementia and the mixture thereof. Cerebrovascular dementia appears as secondary disease after cerebrovascular disease. As one of the causes of the disease is regarded the occurrence of neuronal damage in the brain resulting from ischemic condition at an attack. Accordingly, it is expected that agents having protective effects on neuronal damage in the brain after a transient ischemia, that is, neuroprotective activity, are useful for the prevention and treatment of senile dementia.
3-Sulfamoylmethyl-1,2-benzisoxazole and its alkali metal salts are known to be useful as an anticonvulsant agent [Arzneim.-Forsch./Drug Res., 30 (I), 477-483 (1980) and U.S. Pat. No. 4,172,896]. On the other hand, it is reported that phenytoin and carbamazepine, typical anticonvulsants, are effective against cerebral hypoxia [Arch. int. Pharmacodyn., 286, 282-298 (1987)].
At present, hypnonarcotic agents such as phenobarbital and thiobarbital are used in the treatment of ischemic brain damage. Their neuroprotective activity is attributed to a decrease of energy demand of neurons themselves, which results from the depression of the activity of central nervous system by them. In other words, hypnonarcotic agents exhibit neuroprotective activity by suppressing the function of neurons below physiological levels. Accordingly, for attaining the desired effect, it is necessary to administer a hypnonarcotic agent at a dose sufficient to exhibit depressant effects on the whole central nervous system. As a result, the brain stem system regulating respiration or blood pressure is depressed so that an adverse effect on respiratory or circulatory organ accompanies the protective effect of hypnonarcotic agents as a side effect.
The present inventors have found that 3-sulfamoylmethyl-1,2-benzisoxazole and its alkali metal salts have potent protective effects on cerebral hypoxia without being accompanied by such side effects as hypnonarcotic agents, and that they have an extremely potent protective effect on neuronal damage in the hippocampus which is an important region in terms of controlling emotion, memory, and the like, in contrast to the relatively weak effect of phenytoin and carbamazepine.